Compounds as modulators of a mutant CFTR protein and their use for treating diseases associated with CFTR protein malfunction

Abstract

An exemplary embodiment relates to novel protein modulators capable of altering function of the mutant CFTR protein and their use for treating diseases associated with CFTR protein malfunction. The invention provides compositions, pharmaceutical preparations and methods of correcting the cellular alteration of a mutant CFTR protein wherein the CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.

We claim: 
     
       1. A pharmaceutical composition comprising:
 a compound of general formula (IIIb) used for the manufacture of a medication for the treatment of diseases associated with CFTR protein malfunction: 
 
       
         
           
           
               
               
           
         
       
       its tautomers, E and Z geometric isomers, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof or complexes thereof;
 wherein any occurrence of Z 1  independently represents the following optional substituents, —OR B , —OC(═O)R C , —OC(═O)OR B , —OC(═O)N(R A )R A ′, —C(═O)R C , —C(═O)N(R A )R A ′, —C(═O)N(OR B )R A , —C(═O)OR B , —C(═S)R C , —C(═O)C(═O)R C , —CH 2 OR B , —CH 2 CH 2 OR B , —CH 2 N(R A )R A ′, —CH 2 CH 2 N(R A )R A ′, —CH 2 OCH 2 R C , —CH 2 N(R A )CH 2 R C , —SR D , —S(═O)R D , —SO 2 R D , —SO 2 N(R A )R A ′, —SO 3 R B , —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )C(═O)N(R A ′)R A ″, —N(R A )SO 2 R D , —N(R A )SO 2 N(R A ′)R A ″, —N(R A )R A ′, —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )N(R A ′)R A ″, —N(R A ′)N(R A )C(═O)R C , —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —SCN, —SO 2 CN, —F, Cl, —Br, —I, —C n H 2n R C  which is branched or unbranched wherein n is an integer from 1 to 5; —C n H (2n-2) R C  in E or Z geometrical conformation which is branched or unbranched wherein n is an integer from 2 to 5; —C n H (2n-4) R C  which is branched or unbranched wherein n is an integer from 2 to 5, —PO 3 H 2 , or —OPO 3 H 2 ; 
 wherein R A , R A ′, R A ″ are each independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, and —OH; 
 wherein R B  is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, and —CH 2 I; 
 wherein R C  is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 Cl, —CH 2 Br, —CH 2 I, —F, —Cl, —Br, —I, and —NH 2 ; 
 wherein R D  is independently selected from the group consisting of: —H and lower alkyl group 
 wherein R 5  and R 6  are optional substituents which are independently selected from the group consisting of: OH, NH 2 , COOH, Cl, Br, I, CH 3 , and C 2 H 5 ; 
 wherein R 7  is an optional substituent which is independently selected from the group consisting of: —F, —Cl, —Br, —I, —CH 3 , and —C 2 H 5 ; 
 wherein R 8  is an optional substituent which is independently selected from the group consisting of: —NH 2 , —NHAr, —OH, —CH 2 Ar, —C(═O)Ar, and —OAr; 
 wherein Ar is an aromatic group or heteroaromatic group, and 
 wherein the compound of formula (IIIb) is present in a pharmaceutical composition. 
 
     
     
       2. The pharmaceutical composition according to  claim 1 , wherein the compound has an effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II, and wherein a mutation ΔF508-CFTR, or another mutation of class II are involved in CFTR protein malfunction. 
     
     
       3. The pharmaceutical composition according to  claim 1 , wherein the compound is characterized in that it has effect on CFTR-dependent ion transport across a cellular membrane and/or it has the ability to increase the number of mutant CFTR proteins that reach a cell surface. 
     
     
       4. The pharmaceutical composition according to  claim 1 , wherein the compound is characterized in that it has a stabilizing effect on the structure of the mutant CFTR protein and/or blocks interaction with cellular proteins responsible for the premature degradation of mutant CFTR. 
     
     
       5. The pharmaceutical composition according to  claim 1 , wherein the compound is characterized in that it has an effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II. 
     
     
       6. A pharmaceutical composition comprising:
 a compound used for the manufacture of a medication for the treatment of diseases associated with CFTR protein malfunction: 
 
       
         
           
           
               
               
           
         
       
       its tautomers, E and Z geometric isomers, enantiomers, diastereomers or its pharmaceutically acceptable salts thereof, or complexes thereof, 
       wherein the compound is present in a pharmaceutical composition. 
     
     
       7. The pharmaceutical composition according to  claim 6 , wherein the compound has an effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR or another mutation of class II, and wherein the mutation ΔF508-CFTR or another mutation of class II are involved in CFTR protein malfunction. 
     
     
       8. The pharmaceutical composition according to  claim 6 , wherein the compound is characterized in that it has effect on CFTR-dependent ion transport across a cellular membrane and/or it has the ability to increase mutant CFTR proteins that reach a cell surface. 
     
     
       9. The pharmaceutical composition according to  claim 6 , wherein the compound is characterized in that it has a stabilizing effect on the structure of the mutant CFTR protein and/or blocks interaction with cellular proteins responsible for premature degradation of mutant CFTR protein. 
     
     
       10. The pharmaceutical composition according to  claim 6 , wherein the compound is characterized in that it has an effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II. 
     
     
       11. A method comprising:
 treating a disease associated with CFTR protein malfunction in a patient by administering a therapeutically effective amount of a composition comprising: 
 a compound: 
 
       
         
           
           
               
               
           
         
       
       its tautomers, E and Z geometric isomers, enantiomers, diastereomers or its pharmaceutically acceptable salts thereof, or complexes thereof,
 as a modulator of a mutant CFTR protein to the patient. 
 
     
     
       12. The method according to  claim 11 , wherein the CTFR protein malfunction is a mutation of ΔF508-CFTR. 
     
     
       13. A method comprising:
 treating a disease associated with CFTR protein malfunction in a patient by administering to the patient a therapeutically effective amount of a composition comprising: 
 a compound of general formula (IIIb): 
 
       
         
           
           
               
               
           
         
       
       its tautomers, E and Z geometric isomers, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof or complexes thereof;
 wherein any occurrence of Z 1  independently represents the following optional substituents, —OR B , —OC(═O)R C , —OC(═O)OR B , —OC(═O)N(R A )R A ′, —C(═O)R C , —C(═O)N(R A )R A ′, —C(═O)N(OR B )R A , —C(═O)OR B , —C(═S)R C , —C(═O)C(═O)R C , —CH 2 OR B , —CH 2 CH 2 OR B , —CH 2 N(R A )R A ′, —CH 2 CH 2 N(R A )R A ′, —CH 2 OCH 2 R C , —CH 2 N(R A )CH 2 R C , —SR D , —S(═O)R D , —SO 2 R D , —SO 2 N(R A )R A ′, —SO 3 R B , —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )C(═O)N(R A ′)R A ″, —N(R A )SO 2 R D , —N(R A )SO 2 N(R A ′)R A ″, —N(R A )R A ′, —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )N(R A ′)R A ″, —N(R A ′)N(R A )C(═O)R C , —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —SCN, —SO 2 CN, —F, Cl, —Br, —I, —C n H 2n R C  which is branched or unbranched wherein n is an integer from 1 to 5; —C n H (2n-2) R C  in E or Z geometrical conformation which is branched or unbranched wherein n is an integer from 2 to 5; —C n H (2n-4) R C  which is branched or unbranched wherein n is an integer from 2 to 5, —PO 3 H 2 , or —OPO 3 H 2 ; 
 wherein R A , R A ′, R A ″ are each independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, and —OH; 
 wherein R B  is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, and —CH 2 I; 
 wherein R C  is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 Cl, —CH 2 Br, —CH 2 I, —F, —Cl, —Br, —I, and —NH 2 ; 
 wherein R D  is independently selected from the group consisting of: —H and lower alkyl group 
 wherein R 5  and R 6  are optional substituents which are independently selected from the group consisting of: OH, NH 2 , COOH, Cl, Br, I, CH 3 , and C 2 H 5 ; 
 wherein R 7  is an optional substituent which is independently selected from the group consisting of: —F, —Cl, —Br, —I, —CH 3 , and —C 2 H 5 ; 
 wherein R 8  is an optional substituent which is independently selected from the group consisting of: —NH 2 , —NHAr, —OH, —CH 2 Ar, —C(═O)Ar, and —OAr; 
 wherein Ar is an aromatic group or heteroaromatic group. 
 
     
     
       14. The method according to  claim 13 , wherein the CTFR protein malfunction is a mutation of ΔF508-CFTR.